Diabetes, Lipoproteins and Accelerated Vascular Disease

BACKGROUND:

Diabetes mellitus is associated with a 2-4 fold increase in risk for atherosclerotic
cardiovascular disease. Atherosclerotic cardiovascular disease, particularly coronary artery
disease, is the leading cause of death in diabetics. The study was a subproject within a
program project grant, with Henry Ginsberg as principal investigator. The program project
was part of an institute-initiated study on The Etiology of Excess Cardiovascular Disease in
Diabetes Mellitus. The initiative originated after discussions between NHLBI and the
Juvenile Diabetes Foundation International (JDFI). The Request for Applications (RFA) was
originally issued in October 1994 and resulted in the award of one grant The RFA was
reissued in December 1995 and resulted in the awarding of five program project grants, the
one under discussion among them.

DESIGN NARRATIVE:

The study, subproject 3 within a program project grant, was entitled Atherogenic
Triglyceride Rich Lipoproteins in Diabetes. The subproject examined the atherogenicity of
hypertriglyceridemia in subjects with non-insulin dependent diabetes mellitus (NIDDM).
Subproject 3 tested hypotheses concerning the impact of the size and number of
triglyceride-rich lipoproteins (TGRL) on risk for atherosclerotic cardiovascular disease
(ASCVD) in several human populations. A case-control study of diabetics with or without
coronary artery disease determined if TGRL size and number differed between the groups. In
this study, Whites, Blacks and Hispanics with documented coronary artery disease or with
less than 50 percent coronary stenosis by angiography were recruited. The hypothesis was
tested that increased apoB in small TGRL was associated with coronary artery disease.
Fasting and postprandial blood samples were obtained for measurement of TGRL apoB level,
TGRL TG:apoB ratio, the amount of apoB in apoE-rich TGRL, and retinyl palmitate clearance.
Allelic differences in the apoB, apoE, LPL, and apoCIII genes were examined for effects on
the size and number of TGRL: specific hypotheses were tested regarding the impact of these
alleles.

TGRL size and number were also compared in diabetics with and without carotid
atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) study, in Sioux and Pima
Indian tribes that differed in ASCVD rates, and in Blacks, Whites and Hispanics with a range
of insulin levels and insulin resistance in the Insulin Resistance and Atherosclerosis Study
(IRAS). These studies served both to confirm findings in the case-control study and to
provide the opportunity to investigate diverse populations. The collaboration with IRAS
allowed determination of the effects of insulin resistance and insulin secretory capacity on
TGRL size and number. Finally, experiments with cultured endothelial cells were performed to
determine if small TGRL could cause endothelial dysfunction. PMI-1 and VCAM-1 were markers
of TGRL effects. In the case-control study, plasma PMI and VCAM-1 were measured to examine
their relationship to coronary artery disease and to TGRL size and number.

Dollars awarded were estimated based on the CRISP assignment of $173,249 dollars in FY 1996
for Subproject 3. This was approximately 25 percent of the total dollars awarded and was
used to estimated committed dollars.

Inclusion criteria

- Patients with type 2 diabetes mellitus (DM), defined by medical record diagnosis,
fasting glucose >140 mg/dl, or the use of diabetes medications

- Had a myocardial infarction (MI) any time in the past, a coronary angiogram within
the previous year, or an exercise perfusion scan (stress thallium study) within one
year

- Patients with CAD group, defined by the following criteria: documented prior MI,
PTCA/stent, CABG, or >75% stenosis in any vessel by coronary angiography.

- Patients without CAD group, defined as: the absence of a prior MI and <50% stenosis
in all vessels by coronary angiography within the past year, or the combination of a
normal exercise perfusion scan and the absence of a prior MI or any interventional
cardiac procedures.

Exclusion criteria

- MI or cardiac procedures within the past 3 months

- Diagnoses of cancer, severe congestive heart failure (ejection fraction < 20%),
kidney or liver disease, pancreatitis, other gastrointestinal conditions,

- Laboratory values of creatinine levels > 1.3, abnormal liver function tests, abnormal
CBC, fasting TG > 400 mg/dl, urine protein > 2+ on urinalysis or > 1000 mg/24 h,
abnormal thyroid function tests, body mass index (BMI) > 34 for men and > 37 for
women or BMI < 20 for both sexes

- Age < 35 or > 75 years